This application represents the request for extension of continuously funded work in mechanisms mediating cardiovascular control under normal conditions and in the presence of hypertrophy and heart failure in chronically instrumented animals since 1972. One proposed model that persists is the pressure-overload model of left ventricular hypertrophy LVH), however, with one major modification. The superimposition of rapid ventricular pacing or spontaneous decompensation permits the study of the transition from stable, severe LVH to LVH/Heart Failure (HF), a critically important clinical problem, physiologically in a well characterized large mammalian model. A multidisciplinary team has been assembled to investigate the overall hypotheses and specific aims related to the regulation Ca2+ handling and EC coupling during the development of LVH and transition to HF. One hypothesis is that the transition from stable VH to LVHIHF involves a change in Ca2+ handling, and excitation - contraction (E-C) coupling at the cellular or molecular level, including alterations in L- and T-type Ca2+ currents, and the action potential, which could increase Susceptibility to arrhythmias. Furthermore, the T-type Ca2+ currents in LVH may play a compensatory role. We will examine the regulation of L- and T-type Ca2+ channels electrophysiologically at the myocyte level and also examine the mechanical correlates both in vivo and in isolated myocytes in vitro. In order to understand the mechanisms involved in he alterations in physiology and E-C coupling, it will be necessary to understand the corresponding changes in genomics and proteomics and vice versa. We will investigate genes known to be involved in Ca2+ regulation and also Novel genes, related to Ca2+ regulation, whose function in the heart is less established. In addition, utilizing a unique model in nature, the hibernating woodchuck, which is characterized by elevated Ca2+ stores and responses of phospholamban and phospholamban phosphorylation diametrically opposed to that observed heart failure, allows us to test the hypothesis that elevated SR Ca2+ is protective in response to pressure overload. These aims and hypotheses will be tested by investigators with expertise in physiology in intact animals, isolated myocytes, Ca2+ channels, proteomics and genomics.